5'UTR-mediated regulation of Ataxin-1 expression

Neurobiol Dis. 2020 Feb;134:104564. doi: 10.1016/j.nbd.2019.104564. Epub 2019 Aug 2.


Expression of mutant Ataxin-1 with an abnormally expanded polyglutamine domain is necessary for the onset and progression of spinocerebellar ataxia type 1 (SCA1). Understanding how Ataxin-1 expression is regulated in the human brain could inspire novel molecular therapies for this fatal, dominantly inherited neurodegenerative disease. Previous studies have shown that the ATXN1 3'UTR plays a key role in regulating the Ataxin-1 cellular pool via diverse post-transcriptional mechanisms. Here we show that elements within the ATXN1 5'UTR also participate in the regulation of Ataxin-1 expression. PCR and PacBio sequencing analysis of cDNA obtained from control and SCA1 human brain samples revealed the presence of three major, alternatively spliced ATXN1 5'UTR variants. In cell-based assays, fusion of these variants upstream of an EGFP reporter construct revealed significant and differential impacts on total EGFP protein output, uncovering a type of genetic rheostat-like function of the ATXN1 5'UTR. We identified ribosomal scanning of upstream AUG codons and increased transcript instability as potential mechanisms of regulation. Importantly, transcript-based analyses revealed significant differences in the expression pattern of ATXN1 5'UTR variants between control and SCA1 cerebellum. Together, the data presented here shed light into a previously unknown role for the ATXN1 5'UTR in the regulation of Ataxin-1 and provide new opportunities for the development of SCA1 therapeutics.

Keywords: 5′untranslated region; Alternative splicing; Ataxin-1; Cerebellum; Post-transcriptional gene regulation; Spinocerebellar ataxia type 1; Upstream AUG.

MeSH terms

  • 5' Untranslated Regions / physiology*
  • Ataxin-1 / genetics*
  • Ataxin-1 / metabolism*
  • Cerebellum
  • Gene Expression Regulation / physiology*
  • Humans
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Spinocerebellar Ataxias*


  • 5' Untranslated Regions
  • ATXN1 protein, human
  • Ataxin-1
  • Protein Isoforms